Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala

Brexanolone (allopregnanolone), was recently approved by FDA for the treatment of post-partum depression. Despite our understanding of neurosteroids’ role as positive allosteric modulators (PAMs) of GABAA receptors, we do not fully understand how allopregnanolone exerts these antidepressant effects. In an effort to do so, we test whether allopregnanolone can alter network states in brain regions implicated in mood. We demonstrate that synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), which have similar molecular pharmacology to allopregnanolone, alter oscillations across species. Acute allopregnanolone treatment confers anxiolytic behavior and enhances basolateral amygdala (BLA) high-theta oscillations (6-12 Hz) through delta-containing GABAA receptors present on BLA parvalbumin (PV+) interneurons in mice; a mechanism distinct from other GABAA PAMs, such as benzodiazepines. Further, we show that, the BLA network ex-vivo can self-sustain oscillations under PV+ interneuron control. Our findings suggest that neuroactive steroid signaling may mediate affective switching by enhancing tonic inhibition on BLA PV+ interneurons and promote a shift in the network and behavioral state.